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Biomedical subjects

L Lumeng

Publications and source records attributed to L Lumeng.

At least 163 records · Page 9Linked to original sources
PubMed1988

Pharmacology of alcohol preference in rodents.

In alcoholism research, two fundamental and closely related questions are: "Why do people drink?" and "Why do some people drink too much?" Humans voluntarily drink alcoholic beverages or self-administer alcohol, more often than not, in a social setting. Environmental factors and how individuals react to them can, therefore, have powerful influences on drinking behavior. On the other hand, the neuropsychopharmacological actions of ethanol and how different individuals react to them can be important biological determinants. Ethanol's action is biphasic, i.e., it can be reinforcing (rewarding) in the low concentration range, but aversive at high concentrations. Perception by the individual of the reinforcing actions of ethanol might be expected to maintain alcohol-seeking behavior, whereas aversive effects would be expected to extinguish this behavior. Identification of the environmental and biological variables that promote and maintain alcohol-seeking or alcohol self-administration behavior is key to our understanding of the disorder alcoholism itself.

Alcoholism↗
PubMed1987

Persistence of tolerance to a single dose of ethanol in the selectively-bred alcohol-preferring P rat.

The persistence of tolerance to a single dose of ethanol was examined in the selectively-bred alcohol-preferring P line of rats. Tolerance was measured by a test that required trained rats to jump onto a descending platform to avoid footshock. On day 0, each trained rat received a single IP injection of 2.5 g ethanol/kg body weight and was tested every 15 minutes for recovery to a criterion of 75% of pre-alcohol training performance. The second ethanol injection of 2.5 g/kg and testing were carried out seven days later for one group (n = 12), and 14 days later for another group (n = 12). Tolerance was assessed by the differences in time required to recover to criterion performance and blood alcohol concentrations (BACs) at time of recovery on day 0 vs. day 7 and day 14. The mean recovery times and BACs on day 0 were 156 +/- 5 minutes and 222 +/- 6 mg%, respectively. The group injected on day 7 exhibited shorter recovery times of 113 +/- 4 minutes and higher BACs at recovery of 261 +/- 4 mg%, while the group injected on day 14 did not show any significant differences from the values obtained on day 0. In a second experiment, the persistence of tolerance in P rats was compared with that of rats from the alcohol-nonpreferring NP line and of stock Wistar rats (n = 6/group). All rats were trained and tested for recovery to criterion after 2.5 g ethanol/kg on day 0 as described for the first experiment. The rats were then injected with ethanol and tested for tolerance on three subsequent occasions.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗
PubMed1987

Chronic ethanol tolerance through free-choice drinking in the P line of alcohol-preferring rats.

The objective of this study was to determine if the selectively bred P line of alcohol-preferring rats would develop behavioral (neuronal) tolerance with free-choice drinking of ethanol. Adult, male P rats were divided into four groups. One group (FCE) received food, water and a 10% (v/v) ethanol solution ad lib, while the control group (C) had only food and water. The other two groups received either a liquid diet containing 5% (v/v) ethanol (LDE) or a control liquid diet (LDC). All groups were kept on their respective feeding regimens for 14 days. The mean (+/- SEM) ethanol intakes for the FCE and LDE groups were 6.8 +/- 0.5 and 9.9 +/- 0.4 g ethanol/kg body wt./day, respectively. A shock-motivated jumping task was used to test for tolerance. Each rat received an IP injection of 2.5 g ethanol/kg and was tested every 15 minutes for recovery to a criterion of 75% of the performance level achieved with training. All rats were tested twice, once on the day before beginning their feeding regimens (day 0) and again 14 days later. Tolerance was assessed from differences in time of recovery to criterion performance and in blood alcohol concentrations (BACs) at recovery on day 0 vs. day 14. The mean recovery times for the C, FCE, LDC, and LDE groups on day 0 were 177 +/- 6, 170 +/- 6, 143 +/- 10 and 153 +/- 13 minutes, respectively, and the BACs were 219 +/- 6, 222 +/- 5, 220 +/- 19 and 214 +/- 6 mg%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗
PubMed1987

Contents of monoamines in forebrain regions of alcohol-preferring (P) and -nonpreferring (NP) lines of rats.

The contents of monoamine neurotransmitters and metabolites were assayed in the frontal cortex, nucleus accumbens and anterior striatum of rats from the selectively bred alcohol-preferring P and nonpreferring NP lines. Lower levels of serotonin (20-30%) in all three brain regions of P as compared with NP rats lends support to the hypothesis that a decreased metabolic activity and/or innervation by serotonin neurons is associated with the abnormally high volitional intake of ethanol. Of additional interest, however, were the approximately 25% lower contents of dopamine and its major metabolites in the nucleus accumbens of the P rats. This observation may indicate that P rats have a specific deficiency in the dopaminergic projections from the ventral tegmental area to the nucleus accumbens and, since the accumbens is an important structure in brain reward circuitry, it might also be an important determinant of the excessive volitional intake of alcohol by P rats.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Alcoholism: is it a model for the study of disorders of mood and consummatory behavior?

Depression, eating disorders, and carbohydrate craving are frequently seen in alcoholics or recovering alcoholics. Accordingly, these disorders may share some mediating pathways. It is now well-established that there is a genetic predisposition to alcoholism. Through genetic means, our laboratory has developed an animal model of alcoholism. Free-fed Wistar rats were selectively bred for the traits of alcohol-preference (the P line) and non-preference (the NP line). After more than 20 generations of selection, the lines show a stable difference of more than six-fold in voluntary ethanol consumption. We have now shown that the P line satisfies all the perceived requirements of an animal model of alcoholism. One major discovered difference between the P and the NP line is the lowered content of serotonin in certain brain regions of the P rats. Interestingly, fluoxetine curbs the alcohol-seeking behavior of the P rats; variation in the carbohydrate content of the diet, however, does not modify voluntary ethanol intake. The P rats are similar in body weight to the NP rats, but are more active in a novel environment than the NP rats.

Alcohol Drinking↗
PubMed1987

Alcohol preference and regional brain monoamine contents of N/Nih heterogeneous stock rats.

The N/Nih heterogeneous stock rats were tested for alcohol drinking behavior. Rats that met criteria for high (greater than 5.0 g ethanol/kg body weight/day) and low (less than 0.5 g/kg/day) alcohol consumption were chosen, and the regional brain contents of monoamine neurotransmitters were determined in these animals. The primary finding was a lower content of serotonin and 5-hydroxyindoleacetic acid in the thalamus and hypothalamus of the high alcohol preferring N/Nih rats as compared with the low preferrers. The high preferrers were also found to have a lower content of dopamine and norepinephrine in the thalamus. The findings support the hypothesis that an inverse relationship exists between the density and/or metabolic functioning of regional brain serotonin systems and alcohol preference.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Naloxone attenuation of voluntary alcohol consumption.

The effect of naloxone on voluntary alcohol consumption was examined in two lines of rats which have recently been selectively bred for oral alcohol preference (High Alcohol Drinking or HAD line) or aversion (Low Alcohol Drinking or LAD line). Genetic differences in brain met-enkephalin content were examined in two additional lines of rats which have been genetically selected for oral alcohol preference (Alcohol-Preferring or P line) or aversion (Alcohol-Nonpreferring or NP line).

Alcohol Drinking↗
PubMed1987

Rodent lines selected for factors affecting alcohol consumption.

The selectively bred alcohol-preferring P and alcohol-nonpreferring NP lines of rats have been used to study the biology of alcohol-seeking behavior. The P rats satisfy all the perceived criteria for an animal model of alcoholism: free-fed animals voluntarily drink alcoholic solutions (10-30% v/v) to intoxication; they acquire metabolic and neuronal tolerance, and develop physical dependence; they work (bar-press) to obtain the alcohol and self-administer ethanol intragastrically. Drinking in the P rats ceases when blood alcohol concentrations (BACs) reach 50-70 mg%, but BACs subsequently rise to as high as 270 mg%. BACs, 15-70 mg%, elicit increased spontaneous motor activity in the P rats, but not in the NP rats. Acute tolerance to a single hypnotic dose of ethanol develops more rapidly and persists many days longer in the P than in the NP rats. These differences in the effects of ethanol may underlie the disparate alcohol drinking behaviors of the P and NP rats. The P rats also exhibit lowered serotonin levels in certain brain regions. Serotonin reuptake inhibitors curtail the alcohol drinking of the P rats, suggesting a role for serotonin in alcohol preference.

Alcohol Drinking↗
PubMed1986

The development of metabolic tolerance in the alcohol-preferring P rats: comparison of forced and free-choice drinking of ethanol.

Experiments were performed to determine whether metabolic tolerance to alcohol develops in the alcohol-preferring P rats during free-choice drinking. In Experiment 1, alcohol elimination rates (AERs) in female Wistar and P rats were measured as a function of age from 26 to 180 days old. AERs calculated as mmol hr-1 per kg body weight fell with age, whereas AERs expressed as mmol hr-1 per rat increased to reach a constant value after 60 days of age. These data indicate that the chronic effects of ethanol on AER are most easily interpreted if experiments are performed in animals 60 days of age or older and AERs are calculated as mmol hr-1 per rat. In Experiments 2 and 3, P female rats were exposed to alcohol for 6-7 weeks either by free-choice drinking or by forced feeding with liquid diets. With free-choice drinking of alcohol, solid food containing 31 percent of the calories as protein, 10 percent ethanol (v/v) and water were made available ad lib. The liquid diets used for forced ethanol feeding were the Bio-Serv-711 diet, a protein-supplemented Bio-Serv-711 diet and the AIN diet and they contained 18, 32 and 22 percent calories as protein, respectively. When compared with pair-fed or ad lib controls, all the P rats exposed to alcohol by either free-choice or forced-feeding exhibited increased AERs (i.e., metabolic tolerance) after 6-7 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Dehydrogenase↗
PubMed1986

Effect of low dose ethanol on spontaneous motor activity in alcohol-preferring and -nonpreferring lines of rats.

To determine if behavioral arousal may be associated with ethanol preference, the effects of low to moderate doses of ethanol on spontaneous motor activity (SMA) were studied in the selectively bred alcohol-preferring (P) and -nonpreferring (NP) lines of rats as well as in the Maudsley Reactive (MR/N) and Nonreactive (MNR/N) strains. Alcohol-naive rats had food and water available ad lib, but food was removed 24 hr before and during activity testing. After an intraperitoneal injection of saline (5 ml) or ethanol (0.12 to 1.5 g/kg), SMA was monitored every three min for 30 min in an electronic activity monitor. The P and MR/N rats exhibited increased SMA after doses of 0.12 and 0.25 g/kg. Both the NP and MNR/N rats failed to show increased SMA at any ethanol dose. Moderate doses of ethanol, 1.0 and 1.5 g/kg, consistently depressed SMA in all lines/strains. In 24 hr-fasted rats, increased SMA occurred within 6-12 min after injection, but free-fed rats exhibited increased SMA 12-24 min after an ethanol dose of 0.25 g/kg. Free-choice drinking scores (10% ethanol (v/v) versus water) for the P, MR/N, MNR/N and NP rats were 6.6 +/- 0.5, 4.9 +/- 0.8, 2.2 +/- 0.7 and 1.4 +/- 0.3 g ethanol/kg body wt/day (mean +/- SEM), respectively. The data indicate a positive relationship between ethanol preference and ethanol-induced motor stimulation and suggest that hyperactivity may be an expression of the positive reinforcing effect of ethanol for alcohol-preferring rats.

Animals↗
PubMed1986

Transport and metabolism of vitamins.

Although the biochemical roles of most vitamins in the body are reasonably well understood, our knowledge of how the body transports and metabolizes the vitamins is incomplete. This paper summarizes the information available on riboflavin, vitamin B-6, biotin, vitamin D, vitamin C, and pantothenic acid. As might be expected on the basis of the diverse chemistry and biology of these substrates, the body has quite unique mechanisms for handling each of them.

Animals↗
PubMed1986

Studies on an animal model of alcoholism.

Past and ongoing studies indicate that the selectively bred P line of rats satisfies virtually all the suggested criteria for an animal model of alcoholism. They attain pharmacologically active levels of BAC and develop tolerance and physical dependence with voluntary oral ethanol ingestion, while in the free-feeding state. Ethanol is positively reinforcing to the P rats and consumption appears to be directed by the post-ingestive, pharmacological effects of ethanol, as revealed by the intragastric self-administration studies. Some interesting differences between the P and the NP lines have been uncovered. They differ in the content of serotonin in several brain regions and they respond differently to ethanol. The P rats develop acute tolerance to sedative-hypnotic doses of ethanol more rapidly than do the NP rats, and they exhibit stimulation with low doses of ethanol. These differences suggest hypotheses on mechanisms underlying alcohol-seeking behavior which can now be tested experimentally. It should be emphasized, however, that the described findings are the product of but a single genetic experiment. Clearly, replication is needed, and we are currently doing this, using a better defined, heterogeneous stock of rats. This one experiment, however, has demonstrated the feasibility of developing animal models of alcoholism and offers hope that the genetic and biological basis of alcohol-seeking behavior can be explored in the laboratory. The screening and testing of pharmacological agents able to deter alcohol-seeking behavior is an obvious practical application of this model.

Alcohol Drinking↗
PubMed1985

The measurement of plasma vitamin B6 compounds: comparison of a cation-exchange HPLC method with the open-column chromatographic method and the L-tyrosine apodecarboxylase assay.

A cation-exchange high-performance liquid chromatographic (HPLC) method was found to be comparable to the open-column (OCC) method for measuring six different B6 compounds in human plasma and the L-tyrosine apodecarboxylase (LTD) assay for pyridoxal-P (PLP). Plasma samples were obtained from 9 subjects before and after 7 days of pyridoxine (PN) supplementation. PLP, pyridoxal (PL) and 4-pyridoxic acid (4-PA) were the major B6 compounds in plasma and the only compounds which increased after supplementation. The coefficients of correlation between any 2 of the 3 methods in measuring plasma PLP were greater than 0.93, and between HPLC and OCC in quantifying PL and 4-PA were 0.82 and 0.63, respectively. With the low plasma levels of pyridoxamine-P, PN and pyridoxamine, the results from OCC were consistently higher than those from HPLC. However, recoveries of spiked B6 compounds in plasma by these methods were between 84 to 105 percent for all the 5 vitamers and 4-PA.

Adult↗
PubMed1985

Effect of glucagon on hepatic taurocholate uptake: relationship to membrane potential.

Since glucagon can hyperpolarize hepatic plasma membrane and stimulate biliary bile acid secretion in vitro, we studied the effect of glucagon on taurocholate uptake and its relationship to plasma membrane potential in isolated rat hepatocytes. [14C]taurocholate uptake was linear through 1 min and contained a saturable sodium-dependent and a nonsaturable sodium-independent component. Km of taurocholate uptake by the sodium-dependent system was 18.4 microM. Hill coefficient for Na+ was 2.59 and for taurocholate was 1.1, suggesting that the stoichiometry is 2 Na+:1 bile acid. Stimulation of taurocholate uptake by glucagon was limited to the sodium-dependent component, detected within 5 min of hormone exposure, and was maximum at 30 min. Glucagon, from 10(-8) to 10(-5) M, stimulated taurocholate uptake and hyperpolarized concurrently the plasma membrane potential. Because valinomycin produced a dose-related depolarization of plasma membrane potential, this agent was used to counteract the effects of glucagon. With 10(-6) M glucagon, valinomycin (10(-10) M) depolarized membrane potential from -35.50 to -28.00 mV and inhibited taurocholate uptake from 60% above the control rate to 5% below. These data strongly suggest that taurocholate uptake by isolated hepatocytes is an electrogenic process, and its stimulation by glucagon may be mediated by changes in plasma membrane potential.

Animals↗
PubMed1985

Relationship between body store of vitamin B6 and plasma pyridoxal-P clearance: metabolic balance studies in humans.

Factors that regulate the clearance of plasma pyridoxal-P (PLP) are unknown. Four volunteers were given a diet supplying approximately 12 mumol pyridoxine (PN) per day. The pharmacokinetics of plasma PLP clearance were measured in these subjects before and after 4 weeks of intravenous PN supplementation (122 mumol/day). Urinary B6 excretion, mainly as 4-pyridoxic acid (4-PA), increased progressively after initiation of PN supplementation until a new steady state was reached on day 10 of supplementation, whereupon greater than 93% of the daily injected PN could be recovered in the urine. Hence, urinary excretion is almost the sole route for vitamin B6 elimination. Fasting plasma PLP concentration increased with supplementation and also reached a new steady state at this time. When supplementation was terminated, urinary B6 excretion decreased in 5 days to an amount only slightly higher than that before supplementation. This amount was maintained for 2 months. By comparison, plasma PLP decreased more slowly and remained considerably higher than the presupplementation level for the rest of the study. These data confirm that urinary 4-PA excretion is a better indicator of B6 intake than is plasma PLP content, whereas plasma PLP content is a better indicator of the body store of the vitamin. Plasma clearance and volume of distribution of PLP decreased significantly after supplementation, but half-life t 1/2 did not change. Plasma clearance of PLP, therefore, is dependent on the vitamin B6 status of an individual.

Adult↗
PubMed1984

Rate-determining factors for ethanol metabolism in fasted and castrated male rats.

The effects of castration and fasting upon the alcohol elimination rate, liver alcohol dehydrogenase (LADH) maximum activity (Vmax), and hepatic concentrations of ethanol, acetaldehyde, and free NADH during ethanol oxidation were examined in male Wistar rats. Castration increased the Vmax of LADH and, to a lesser extent, the alcohol elimination rate in vivo. On the other hand, fasting reduced the Vmax of LADH and the alcohol elimination rate in sham-operated and castrated rats but it did not nullify the effect of castration. Castration produced small but significant changes in the hepatic concentrations of ethanol, acetaldehyde and free NADH in fed rats during ethanol oxidation. Fasting also caused significant increases in the concentration of free NADH during alcohol oxidation in both the sham-operated and castrated groups. The ratio of the steady-state velocities of LADH in situ to the maximum velocities of LADH (v/Vmax) under the different experimental conditions was calculated by using the steady-state rate equation for the enzyme mechanism of rat LADH and its kinetic constants. The calculated v/Vmax ratios were 50-62%, indicating that LADH activity was limited to about the same extent by its substrates and products under these conditions and that the changes in alcohol elimination rates produced by fasting and castration mainly reflected changes in the Vmax of LADH. The calculated steady-state velocities in situ (v) were 14-28% lower than the measured rates of alcohol elimination in vivo. The extent of agreement is probably acceptable in view of the assumptions needed to determine the free NADH concentration in liver and the existence of non-LADH-related processes for alcohol elimination in vivo.

Alcohol Dehydrogenase↗
PubMed1984

Intragastric self-infusion of ethanol by ethanol-preferring and -nonpreferring lines of rats.

An ethanol-preferring line of rats, developed by selective breeding, consumed as much as 9.4 +/- 1.7 grams of ethanol per kilogram of body weight per day through intragastric self-infusions, yielding blood ethanol concentrations of 92 to 415 milligrams per 100 milliliters. By contrast, the ethanol- nonpreferring line self-administered only 0.7 +/- 0.2 gram per kilogram per day. These findings indicate that the reinforcing effect of ethanol is postabsorptive and is not mediated by the drug's smell or taste. Hence the ethanol-preferring line of rats may be suitable animal model of alcoholism.

Alcohol Drinking↗